The major objective of this program is to increase our understanding of normal and abnormal gene function in human cells at various levels of biological organization ranging from the molecular and cellular level to that of the embryo, infant, child and adult patient. In the process, a number of secondary goals of both basic biomedical science and applied clinical medicine will be achieved through a cascading interaction of the different phases of the program. The persistence of genetically-determined specific enzyme defects in cultured human fibroblasts or amniotic cells provides the physical bridge for a wide range of collaborative work between clinicians and basic scientists. Such defects can be used as biochemical markers for studies of basic genetic mechanisms of mammalian cells. Knowledge of the normal function of mammalian cells will be further extended through studies of the aberrations in such function produced by well-defined biochemical mutations accompanying a variety of human metabolic diseases. Detection of the same biochemical defects in fetal amniotic cells permits a new prevention approach for the control of over two dozen seriously incapacitating hereditary diseases through prenatal diagnosis and selective management of gestation. The participants in this program come from the departments of Medicine, Pediatrics, Pathology, Biology, Chemistry and Neurosciences, and are experienced in application of technical disciplines including protein chemistry, computer technology, enzymology, cell culture, immunochemistry, neurochemistry, genetics and a variety of techniques involved in cell biology. There is substantial interdigitation between the various research proposals and each major research area will require the collaborative efforts of several principal participants. This program is designed to allow these individuals to continue their research efforts in an expanded collaborative environment.